Our recent studies show that insulin resistance (IR) severely impairs arterial dilator function in the cerebral circulation via mechanisms involving the sustained production and actions of reactive oxygen species (ROS). Our overall hypothesis is that: Vascular dysfunction of the cerebral circulation in IR is due to augmented ROS levels from enhanced activity of the NADPH oxidase system. Furthermore, we speculate that differences are present in ROS signaling occur in endothelium and VSM; that statins directly modulate NADPH oxidase activity or indirectly act via a reduction in vascular inflammation; that ROS scavenging by superoxide dismutase or gene transfer of EcSOD reverses vascular dysfunction; that neurological damage is enhanced in IR; and that acute administration of statins can limit IR-enhanced ischemic damage in IR. We have created 2 specific aims to test the following hypotheses and speculations in the cerebral circulation and brain in a genetic model of IR (Zucker obese rats): Specific Aim 1. Elucidation of mechanisms of deranged arterial function of the cerebral circulation in IR. We will test the hypothesis that IR impairs endothelium- and VSM potassium channel-dependent function of cerebral arteries via vascular production and actions of ROS. First, we will assess the role of ROS in vascular dysfunction in IR using pharmacological agents and gene transfer approaches. Second, we will determine the metabolic source and characteristics of ROS involved in dysfunction of cerebral vessels of IR rats. Third, we will document, using electrophysiological approaches, the effects of ROS on potassium channels-dependent membrane potential characteristics in cerebral arteries from IR rats. Fourth, we will examine the effects of IR on extent of neurological injury following experimental strokes. Specific Aim 2. Examination of mechanism of statins in reversing vascular dysfunction in IR. We will test the hypothesis that statins directly modulate NADPH oxidase activity in IR. First, we will assess the dynamics of statin effects on vascular responsiveness in IR. Second, we will determine the effects of statins on indices of vascular inflammation and ROS production in cerebral arteries. Third, we will examine the effects of statins and IR on VSM membrane characteristics. Fourth, we will examine the effects of statins on the extent of stroke damage in IR. We believe that our results will lead to new therapies that will help patients with insulin resistance and vascular dysfunction. [unreadable] [unreadable] [unreadable]